From Lead to Drug Utilizing a Mannich Reaction: The Topotecan Story

Bracher, Franz; Tremmel, Tim

doi:10.1002/ardp.201600236

Cited by 16 publications

(8 citation statements)

References 39 publications

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“…Topotecan (TPT) is a derivative of camptothecin which originates from the Camptotheca acuminata (108) and is used in the second-line treatment of ovarian cancer. A clinical trial demonstrated that TPT can downregulate HIF-1a in solid advanced tumours (109).…”

Section: Molecules Suppressed Ovarian Cancer Progression By Directly or Indirectly Downregulating Hif-1amentioning

confidence: 99%

HIF-1α Is a Rational Target for Future Ovarian Cancer Therapies

Wang

et al. 2021

Front. Oncol.

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Ovarian cancer is the eighth most commonly diagnosed cancer among women worldwide. Even with the development of novel drugs, nearly one-half of the patients with ovarian cancer die within five years of diagnosis. These situations indicate the need for novel therapeutic agents for ovarian cancer. Increasing evidence has shown that hypoxia-inducible factor-1α(HIF-1α) plays an important role in promoting malignant cell chemoresistance, tumour metastasis, angiogenesis, immunosuppression and intercellular interactions. The unique microenvironment, crosstalk and/or interaction between cells and other characteristics of ovarian cancer can influence therapeutic efficiency or promote the disease progression. Inhibition of the expression or activity of HIF-1α can directly or indirectly enhance the therapeutic responsiveness of tumour cells. Therefore, it is reasonable to consider HIF-1α as a potential therapeutic target for ovarian cancer. In this paper, we summarize the latest research on the role of HIF-1α and molecules which can inhibit HIF-1α expression directly or indirectly in ovarian cancer, and drug clinical trials about the HIF-1α inhibitors in ovarian cancer or other solid malignant tumours.

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Section: Molecules Suppressed Ovarian Cancer Progression By Directly or Indirectly Downregulating Hif-1amentioning

confidence: 99%

HIF-1α Is a Rational Target for Future Ovarian Cancer Therapies

Wang

et al. 2021

Front. Oncol.

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“…This stabilizes TOP1cc and prevents further religation of the broken DNA. When replication and transcription machineries encounter the trapped TOP1cc, DNA damage is generated, triggering cell death. , To date, four well-known camptothecin TOP1 inhibitors (Figure 2S, Supporting Information) have been approved for clinical treatment of cancers, including irinotecan ( 2 ) and topotecan ( 3 ), approved by the FDA, − 10-hydroxycamptothecin ( 4 , HCPT, in China), and belotecan ( 5 , in South Korea). ,, Therefore, TOP1 is a validated target for the discovery of antitumor agents. ,− …”

Section: Introductionmentioning

confidence: 99%

Discovery, Synthesis, and Evaluation of Oxynitidine Derivatives as Dual Inhibitors of DNA Topoisomerase IB (TOP1) and Tyrosyl-DNA Phosphodiesterase 1 (TDP1), and Potential Antitumor Agents

et al. 2018

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Tyrosyl−DNA phosphodiesterase 1 (TDP1) is a recently discovered enzyme repairing DNA lesions resulting from stalled topoisomerase IB (TOP1)−DNA covalent complex. Inhibiting TDP1 in conjunction with TOP1 inhibitors can boost the action of the latter. Herein, we report the discovery of the natural product oxynitidine scaffold as a novel chemotype for the development of TOP1 and TDP1 inhibitors. Three kinds of analogues, benzophenanthridinone, dihydrobenzophenanthridine, and benzophenanthridine derivatives, were synthesized and evaluated for both TOP1 and TDP1 inhibition and cytotoxicity. Analogue 19a showed high TOP1 inhibition (+++) and induced the formation of cellular TOP1cc and DNA damage, resulting in cancer cells apoptosis at nanomolar concentration range. In vivo studies indicated that 19a exhibits antitumor efficiency in HCT116 xenograft model. 41a exhibited additional TDP1 inhibition with IC 50 value of 7 μM and synergistic effect with camptothecin in MCF-7 cells. This work will facilitate future efforts for the discovery of natural productbased TOP1 and TDP1 inhibitors.

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“…In conjunction with our previous methods, we have thus far developed tools to functionalize this highly complex natural product at C5, C6 and C8 with precision demonstrating the unique power of site selective C–H activation 22 , 29 . Notably, the structural modifications at these positions through semi-synthesis had led to the discovery of drugs, such as topotecan and irinotecan 30 .…”

Section: Resultsmentioning

confidence: 99%

Differentiation and functionalization of remote C–H bonds in adjacent positions

et al. 2020

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Site-selective functionalization of C–H bonds will ultimately afford chemists transformative tools for editing and constructing complex molecular architectures. Towards this goal, developing strategies to activate C–H bonds that are distal from a functional group is essential. In this context, distinguishing remote C–H bonds on adjacent carbon atoms is an extraordinary challenge due to the lack of electronic or steric bias between the two positions. Herein, we report the design of a catalytic system leveraging a remote directing template and a transient norbornene mediator to selectively activate a previously inaccessible remote C–H bond that is one bond further away. The generality of this approach has been demonstrated with a range of heterocycles, including a complex anti-leukemia agent, and hydrocinnamic acid substrates.

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From Lead to Drug Utilizing a Mannich Reaction: The Topotecan Story

Cited by 16 publications

References 39 publications

HIF-1α Is a Rational Target for Future Ovarian Cancer Therapies

HIF-1α Is a Rational Target for Future Ovarian Cancer Therapies

Discovery, Synthesis, and Evaluation of Oxynitidine Derivatives as Dual Inhibitors of DNA Topoisomerase IB (TOP1) and Tyrosyl-DNA Phosphodiesterase 1 (TDP1), and Potential Antitumor Agents

Differentiation and functionalization of remote C–H bonds in adjacent positions

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